Physical Activity Protocols in Non-Alcoholic Fatty Liver Disease Management: A Systematic Review of Randomized Clinical Trials and Animal Models

Non-alcoholic fatty liver disease (NAFLD) is closely associated with other metabolic disease and cardiovascular disease. Regular exercise reduces hepatic fat content and could be the first-line treatment in the management of NAFLD. This review aims to summarize the current evidence of the beneficial effects of exercise training and identify the molecular pathways involved in the response to exercise to define their role in the resolution of NAFLD both in animal and human studies. According to the inclusion criteria, 43 animal studies and 14 RCTs were included in this systematic review. Several exercise modalities were demonstrated to have a positive effect on liver function. Physical activity showed a strong association with improvement in inflammation, and reduction in steatohepatitis and fibrosis in experimental models. Furthermore, both aerobic and resistance exercise in human studies were demonstrated to reduce liver fat, and to improve insulin resistance and blood lipids, regardless of weight loss, although aerobic exercises may be more effective. Resistance exercise is more feasible for patients with NAFLD with poor cardiorespiratory fitness. More effort and awareness should be dedicated to encouraging NAFLD patients to adopt an active lifestyle and benefit from it its effects in order to reduce this growing public health problem.


Introduction
In recent years, the prevalence of obesity has increased along with non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome. Up to 25% of subjects with NAFLD may develop non-alcoholic steatohepatitis (NASH), which is characterized by the accumulation of triglycerides in the liver, inflammation, tissue injury, and apoptosis of hepatocytes, leading to liver cirrhosis and its complications, hepatic decompensation and hepatocellular carcinoma (HCC) [1]. In addition to liver-related mortality, NAFLD is associated with increased mortality associated mostly with cardiovascular disease, diabetes mellitus, and non-liver cancer [2]. The worldwide prevalence of NAFLD is estimated at around 25%, with a higher number of cases reported in South America and the Middle East [3], and is most frequent in men between 40 and 50 years old and women between 60 and 69 years old [4]. Moreover, being overweight during the early life stage is associated with a higher risk of developing NAFLD in adulthood [5]. Notably, 7-20% of subjects with NAFLD exhibit a lean phenotype [6].
Currently, no drug has been approved by international or local regulatory agencies specifically to treat NAFLD. However, there are many drugs approved to treat other com-

Materials and Methods
This systematic review was designed and performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [20]. All the included articles were organized according to whether the study design involved experimental models or human studies. The specific inclusion and exclusion criteria for the experimental models are described in the flow diagram in Figure 1a, while the criteria for human studies are described in Figure 1b.

Eligibility Criteria
We performed an electronic search of the English language literature using PubMed, EBSCO, and Google Scholar databases to identify articles that studied physical activity or exercise programs in the management of NAFLD in adults (>18 years) and animal models. The search followed the keywords used either alone or combined according to the PubMed MeSH database: "Nonalcoholic fatty liver disease", "NAFLD", "non-alcoholic steatohepatitis", "NASH", "obesity", "exercise", "exercise training", "physical activity", "aerobic training" and, "resistance training". The search was restricted to studies published from January 2017 to November 2022 to include the most up-to-date studies on this topic. Healthcare 2023, 11, x FOR PEER REVIEW 3 of 31 (a)

Eligibility Criteria
We performed an electronic search of the English language literature using PubMed, EBSCO, and Google Scholar databases to identify articles that studied physical activity or exercise programs in the management of NAFLD in adults (>18 years) and animal models. The search followed the keywords used either alone or combined according to the PubMed MeSH database: "Nonalcoholic fatty liver disease", "NAFLD", "non-alcoholic steatohepatitis", "NASH", "obesity", "exercise", "exercise training", "physical activity", "aerobic training" and, "resistance training". The search was restricted to studies published from January 2017 to November 2022 to include the most up-to-date studies on this topic.

Inclusion Criteria
For animal studies, we included studies that: (1) measured biomarkers or molecular pathways associated with NAFLD resolution in response to any type of exercise program training, (2) were published in the last 5 years, and (3) were performed in an animal model. For human studies, only randomized controlled trials (RCT) with supervised exercise training that aimed to assess the therapeutic effects of exercise on hepatic steatosis and/or metabolic effects in patients with NAFLD were included.

Exclusion Criteria
In the animal studies, titles and abstracts were screened to exclude the following: reviews; studies without reported details of exercise training protocols, such as time, intensity, duration, or type of exercise; studies combining exercise programs with other interventions, such as diet supplement, nutritional strategies, or drugs administration; studies focusing on different outcomes, such as insulin sensibility, cancer, lipids profile, prothrombotic state; studies of molecular pathways not involved in the resolution of NAFLD; and studies published in languages other than English. For human studies, the use of supplements or drugs as part of the intervention to manage NAFLD, as well as studies with insufficient information on the characteristics of the exercise (type, intensity, frequency, duration per session, and duration of the intervention), were excluded; studies including subjects younger than 18 years old, non-full-text articles, and non-English language studies were also excluded.

Quality Assessment of the RCT Included Studies
The quality of the RCT included was evaluated according to the revised Cochrane riskof-bias tool for randomized studies (RoB 2) [21]. Two authors (FAL and RSR) independently evaluated the quality of trials, and discrepancies were resolved through discussion with a third reviewer (EML) to reach a consensus.

Results
We found a total of 15,925 articles in the initial comprehensive database search. Out of these, 5225 corresponded to experimental studies and 10,700 to human clinical studies. After removing duplicate articles and excluding articles that did not meet the inclusion criteria, 43 animal studies and 14 RCTs were included in this review. Table 1 summarizes the most recent studies regarding exercise training in NAFLD experimental models. Table 2 displays details of the studies about the human response mechanisms to regular exercise in NAFLD, including the exercise protocol training type, intensity, frequency, duration per session, duration of the intervention, as well as the main changes associated with NAFLD.  Aerobic exercise: 5 min warmup period at 9 m/min, 50 min main exercise period at 12 m/min (75% VO 2 max), and a 5 min cooldown period at 9 m/min. (1) WT group,

Exercise Reduces Lipid Accumulation in the Liver
The pathogenesis of NAFLD involves lipid accumulation, inflammation, fibrosis, and disruption of liver homeostasis. Nevertheless, lifestyle changes may reduce the damage and even reverse the common lesions of NAFLD [22,65]. Physical activity modifies the cellular and molecular pathways in patients with hepatic steatosis, though the specific responses remain unclear.
A large number of experimental model studies suggest that exercise intervention may reduce the pathological markers of NAFLD, such as lipid droplet size, fibrosis, vesicular steatosis, hepatocellular ballooning, as well as triglycerides, cholesterol, and glycogen content. In addition, physical activity improves insulin signaling, glucose tolerance, LDL-c, and hepatic β-oxidation [23][24][25][26][27]38,47,66]. The best available evidence of exercise-treated mice showed amendment of NAFLD onset and change in lipogenic gene expression. An aerobic exercise protocol increased the phosphorylation of AMP-activated protein kinase (AMPK), which plays a major role in the regulation of cellular energy balance and increase in the rate of catabolic pathways [67]. Evidence has shown that increase in lipogenic factors, starting with AMPK, could upregulate hepatic carnitine palmitoyl-CoA transferase 1 (CPT1) and adipose triglyceride lipase (ATGL) [23,26,27]. CPT1 modulates the mitochondrial fatty acid β-oxidation pathway [68]. Accordingly, OK et al., Li et al., and Melo et al. have reported an increase in CPT1 in response to aerobic exercise [26,28,29], while Pereira et al. and Bae et al. also reported this after short-term strength training and ladder climbing exercise, respectively [23,66]. The main results were reduction in the size of liver fat droplets and reversal of high-fat diet (HFD)-induced steatosis.

Exercise Reduces Lipid Biosynthesis in the Liver
The accumulation of lipids in the liver is directly linked to hepatic lipogenesis. Several studies have shown the potential effectiveness of exercise programs, mostly aerobic training, in reducing hepatic steatosis by upregulating β-oxidation. Therefore, exercise training may also downregulate lipid synthesis in the liver [24,38].
Fatty acid synthase protein (FAS) plays a role in the synthesis of palmitic acid, while stearoyl CoA desaturase-1 (SCD1) is involved in the formation of monounsaturated fatty acids. Both enzymes catalyze rate-limiting steps in the pathways for fatty acid synthesis. Since the expression of Fasn and Scd1 is increased in mice with fatty liver, they have been proposed as key proteins in NAFLD development. Although the literature provides more evidence about the beneficial effects of aerobic training, short-term strength training also decreases Fasn and Scd1 [39]. Similarly, high-intensity interval training [24], strength training [38], and a mixed exercise protocol [40] have been found to decrease Fas in obese experimental models. Furthermore, other key proteins involved in cholesterol synthesis, such as sterol regulatory element-binding proteins 1 and 2 (SREBP-1/2) and 3-hydroxy-3methylglutaryl-CoA synthase 2 (HMGCS2), are decreased in response to physical activity regardless of the type, intensity, and intervals of exercise [23,24,29,34,40,41].
The scavenger receptor CD36 functions as a central signaling protein in lipid metabolism and has been observed to increase with the use of HFD [43]. In this context, both strength and endurance training have been shown to reduce the obesity-related increase in CD36 [29,38,42]. Fatty-acid-binding protein (FABP) is another protein closely associated with lipid metabolism, which was also downregulated in trained NAFLD mice [33,43].
Other molecules involved in hepatic lipid synthesis have been measured after several exercise protocols. Despite the differences in the protocols, they resulted in a general downregulation in biosynthesis genes. Particularly, high-intensity interval training (HIIT) showed a better effect on the genes related to lipogenesis, such as Pparg, diacylglycerol O-acyltransferase 1 (Dgat1), acetyl-CoA carboxylase alpha (Acaca) and acetyl-CoA carboxylase beta (Acacb), than moderate-intensity continuous training (MIT) [22]; acetyl-CoA carboxylase (Acc) was also reduced when compared to endurance training [24]. However, other authors also showed a decrease in Acc lipogenic gene expression after aerobic endurance training [34], as well as monoacylglycerol O-acyltransferase 1 (Mgat1), which plays a role in the synthesis of diacylglycerol (DAG) and triacylglycerol (TAG) [44].

Exercise Attenuates the Inflammatory Response
The obesity-related accumulation of adipose tissue leads to lipolysis and higher transfer of lipids to different tissues, hence increasing de novo hepatic lipogenesis and decreasing free fatty acid oxidation [69].
In addition, hepatocytes also suffer from high lipid deposition by the transferring of free fatty acids from the adipose tissue, which is usually associated with an inflammatory state [27,47]. Furthermore, the deposition of free fatty acids in the mitochondria may induce the production of reactive oxygen species (ROS), tumor necrosis factor-alpha (TNF-α), as well as other pro-inflammatory cytokines associated with hepatic endoplasmic reticulum (ER) stress [69,70].
NAFLD provokes fibrosis in the context of inflammation-mediated ER stress, proapoptotic cascades, and apoptosis of hepatocytes. Additionally, hepatic ER stress is a major stimulus that induces the recruitment of immune cells to the damaged tissue, which may ultimately lead to terminal organ failure derived from the exacerbated production of proinflammatory cytokines [65,70].
Several experimental studies have shown that exercise intervention, as a first-line treatment for NAFLD, confers significant hepatic protection. Moderate-intensity aerobic exercise differentially modified the inflammatory genes expression p62, Tnf-α, and Il-6 [35]. Moreover, aerobic training also suppressed the inflammation markers TNF-α and IL-6 [48]. It also suppressed the steroid receptor RNA activator (SRA)/JNK/P38 signaling pathway, leading to improved hepatic steatosis and a decrease in the production of inflammatory cytokines [29]. Ruan et al. studied the impact of different levels of exercise intensity and showed that moderate-intensity exercise inhibited hepatocyte apoptosis through a signaling pathway associated with the ER: inositol-requiring enzyme 1α (IRE1)/Jun Nterminal kinases (JNK) and eukaryotic translation initiation factor 2α (eIF2α)/C/EBP homologous protein (CHOP) [47]. Also, Lou et al. investigated the combined effect of aerobic and resistance exercise in GCN2KO mice and showed beneficial effects towards reversing hepatic steatosis by downregulation of eIF2α and activation of transcription factor 4 (Atf4) [25].
NAFLD progression is associated with increased levels of ROS as a marker of poor prognosis. ROS stimulate and promote inflammasome activation through the NACHT, LRR, and PYD domains containing protein 3 (NLRP3), which is highly expressed in the liver and is best characterized by its close association with several chronic diseases [71]. The NLRP3 inflammasome also increases the secretion of the proinflammatory cytokines IL-1β and IL-18 [72]. Aerobic exercise protocols significantly reduce the Nlrp3 multiprotein complex, normalize Il-1β production, and suppress ROS overproduction [49]. Additionally, Gherk et al. showed that aerobic physical activity protects the tissue from macrophage-associated hepatic inflammation in an NAFLD mouse model [50]. Figure 2 shows the effect of exercise training on metabolic pathways in a fatty liver animal model.

Human Model
The results of the quality assessment for the RCT included are displayed in Figure 3. Three studies showed some concerns for risk of bias in their randomization process because they did not provide details of the random allocation sequence. Since physical exercise was the primary intervention among all the RCT included, they did not adopt a blind process and participants were aware of their assigned intervention during the trail. Therefore, all the studies were judged with concerns over possible deviations from the intended interventions and that the assessment of the outcome could be compromised by the knowledge of the intervention received by evaluators and participants. In this way, measures of the outcome were judged with high risk of bias in all the studies. However, no other domains were judged to have high risk of bias.
Physical activity is defined as any movement of the body produced by skeletal muscles that requires more energy than is consumed while resting. In addition, exercise is a subcategory of physical activity defined as planned, structured, and repetitive movements to maintain or improve fitness [73]. Interventions involving the introduction of exercise in lifestyle are an effective strategy to modify the metabolism of hepatic fatty acids and reduce total triglycerides with or without weight loss [74,75].
Exercise is usually classified as aerobic or resistance exercise. Aerobic exercise is generally known as "cardio", which strengthens heart and lung capacity and improves the

Human Model
The results of the quality assessment for the RCT included are displayed in Figure 3. Three studies showed some concerns for risk of bias in their randomization process because they did not provide details of the random allocation sequence. Since physical exercise was the primary intervention among all the RCT included, they did not adopt a blind process and participants were aware of their assigned intervention during the trail. Therefore, all the studies were judged with concerns over possible deviations from the intended interventions and that the assessment of the outcome could be compromised by the knowledge of the intervention received by evaluators and participants. In this way, measures of the outcome were judged with high risk of bias in all the studies. However, no other domains were judged to have high risk of bias.
Physical activity is defined as any movement of the body produced by skeletal muscles that requires more energy than is consumed while resting. In addition, exercise is a subcategory of physical activity defined as planned, structured, and repetitive movements to maintain or improve fitness [73]. Interventions involving the introduction of exercise in lifestyle are an effective strategy to modify the metabolism of hepatic fatty acids and reduce total triglycerides with or without weight loss [74,75].
Exercise is usually classified as aerobic or resistance exercise. Aerobic exercise is generally known as "cardio", which strengthens heart and lung capacity and improves the consumption of oxygen in the body. Aerobic exercise develops mainly type I muscle fibers by increasing their aerobic capacity, while also improving the cardiorespiratory system through the enhancement of microcirculation and arterial compliance, as well as strengthening the respiratory muscles and enhancing myocardial contractility [76]. In addition, it activates lipolysis in several tissues, upregulates the uncoupling of protein-1 and peroxisome proliferator-activated receptor γ pathways, and modifies adipokine levels [7,77].
Resistance exercise, on the other hand, builds up muscle strength and improves muscle tone and bulk [78,79]. This type of exercise promotes the hypertrophy of type II muscle fibers and aims to increase myokine levels, activate glucose transporter 4, caveolins, and the AMP-activated protein pathway, as well as to improve NAFLD through less energy consumption during exercise [77].
Standardizing physical activity prescriptions for NAFLD patients remain a challenge. The EASL-EASO-EASD guidelines for the management of NAFLD recommend 150-200 min per week of moderate-intensity aerobic physical activities in 3-5 sessions while emphasizing the efficacy of resistance training in reducing liver fat and improving musculoskeletal fitness and metabolic risk factors. The guidelines also emphasize the importance of tailoring the training approach to individual patient preferences [18]. The American Association for the Study of Liver Diseases (AASLD) recommends ≥ 150 min/week of moderate-intensity exercise [17], similar to the AGA advice to target 150-300 min of moderate-intensity or 75-150 min of vigorous-intensity aerobic exercise, with consideration of resistance training only as a complement [8]. Moreover, other guidelines only make nonspecific recommendations to increase physical activity [80], attending to patient preferences for aerobic or resistance training to ensure long-term adherence, considering that resistance exercise may be more feasible than aerobic exercise in patients with poor fitness [81].
Although lifestyle interventions, such as changes in diet and exercise to achieve weight loss, remain the cornerstone of NAFLD treatment due to their additive effects in reducing liver fat content, the benefits of each of them have been widely demonstrated independently [17,18,[82][83][84]. Several randomized clinical trials have shown that exercise alone improves NAFLD even without dietary restrictions [85][86][87][88][89][90][91].

Weight Loss in NAFLD
Weight loss is considered a cornerstone to resolve steatosis, NASH, and liver fibrosis [92]; however, exercise can improve NAFLD even without achieving weight loss. Houghton et al. found that 12 weeks of exercise in the absence of weight loss reduced 16% liver fat, 12% visceral fat, and 23% serum triglycerides in patients with biopsy-proven NASH [86]. These results are in line with other studies that demonstrated that an exercise intervention program conferred significant improvements in hepatic stiffness and fat content [85,87,93], glucose homeostasis, and lipid metabolism, regardless of weight loss [91].

Aerobic Exercise vs. Resistance Exercise
Both aerobic and resistance exercises have shown benefits in patients with NAFLD [82,83,86,90], which have led to several RCTs to investigate which one provides greater benefits. Yao et al., evaluated the effects of aerobic and resistance exercise on ALT and blood lipids in patients with NAFLD and they observed significant improvement in HDL in both groups, but only aerobic exercise improved serum ALT and triglycerides after 22 weeks of training [94]. Ghamarchehreh et al. found that aerobic training was more effective than resistance training for improving the lipid profile, particularly total cholesterol, HDL, and LDL in elderly subjects with NAFLD, in an 8-week aerobic and resistance training program [95]. However, Charatcharoenwitthaya et al. found no differences in the reduction in hepatic fat content, abdominal adiposity, or improvement in insulin resistance after 12 weeks of aerobic or resistance training in patients with NAFLD [93].

Aerobic vs. Combined Aerobic plus Resistance Exercise
The response of patients with NAFLD to either aerobic exercise or a combination of aerobic plus resistance exercise was evaluated by Franco et al. They found that after 6 months of exercise training, both groups significantly reduced their NAFLD mean score, but the aerobic exercise program was more effective [89]. Subsequently, Franco et al. evaluated the effects of an aerobic exercise program, an aerobic plus resistance program, a low-glycemic index Mediterranean diet (LGIMD), and their combined effects, in patients with NAFLD, finding that after 90 days, all interventions significantly reduced the NAFLD score, but the LGIMD plus aerobic activity program was associated with the stronger reduction [84].

Moderate-Intensity Continuous Aerobic Training vs. High-Intensity Interval Training
The relative intensity of an exercise is defined as the percentage of utilized aerobic power and is expressed as the percentage of maximum heart rate or percentage of VO2 max. It is important to consider the relative intensity since it is an important factor in the

Aerobic Exercise vs. Resistance Exercise
Both aerobic and resistance exercises have shown benefits in patients with NAFLD [82,83,86,90], which have led to several RCTs to investigate which one provides greater benefits. Yao et al., evaluated the effects of aerobic and resistance exercise on ALT and blood lipids in patients with NAFLD and they observed significant improvement in HDL in both groups, but only aerobic exercise improved serum ALT and triglycerides after 22 weeks of training [94]. Ghamarchehreh et al. found that aerobic training was more effective than resistance training for improving the lipid profile, particularly total cholesterol, HDL, and LDL in elderly subjects with NAFLD, in an 8-week aerobic and resistance training program [95]. However, Charatcharoenwitthaya et al. found no differences in the reduction in hepatic fat content, abdominal adiposity, or improvement in insulin resistance after 12 weeks of aerobic or resistance training in patients with NAFLD [93].

Aerobic vs. Combined Aerobic plus Resistance Exercise
The response of patients with NAFLD to either aerobic exercise or a combination of aerobic plus resistance exercise was evaluated by Franco et al. They found that after 6 months of exercise training, both groups significantly reduced their NAFLD mean score, but the aerobic exercise program was more effective [89]. Subsequently, Franco et al. evaluated the effects of an aerobic exercise program, an aerobic plus resistance program, a low-glycemic index Mediterranean diet (LGIMD), and their combined effects, in patients with NAFLD, finding that after 90 days, all interventions significantly reduced the NAFLD score, but the LGIMD plus aerobic activity program was associated with the stronger reduction [84].

Moderate-Intensity Continuous Aerobic Training vs. High-Intensity Interval Training
The relative intensity of an exercise is defined as the percentage of utilized aerobic power and is expressed as the percentage of maximum heart rate or percentage of VO 2 max. It is important to consider the relative intensity since it is an important factor in the management of NAFLD [73]. Accordingly, physical activities classified as moderateintensity are performed at a relative intensity of 40-60% VO 2 max, while vigorous-intensity activities are performed at a relative intensity of >60% VO 2 max, in line with high-intensity exercise [73].
Several studies have evaluated the impact of the intensity of aerobic exercise on the management of NAFLD. Oh et al., compared the therapeutic effects of resistance training and two intensity modalities of aerobic training, high-intensity interval training (HIIT) and moderate-intensity continuous aerobic training (MICT), for 12 weeks in sedentary obese subjects with NAFLD. All three exercise modalities were equally effective in reducing hepatic fat content, regardless of significant weight and visceral reductions, but only the HIIT group significantly improved their hepatic stiffness associated with restoring the Kupffer cell function and decreased their inflammation markers (leptin and ferritin) [85]. Babu et al. found a significant decrease in blood glucose and waist circumference, as well as an increase in VO 2 max with a 12-week HIIT exercise program compared to a non-intervention group in subjects with NAFLD. In addition, the exercise program group benefited from the loss of weight and promoted positive metabolic changes in amino acids, lipids, and bile acids involved in the regulation of glucose metabolism [91].
Abdelbasset et al. found significant beneficial effects after an 8-week HIIT intervention on intrahepatic triglycerides (IHTG), visceral lipids, and health-related quality of life in diabetic obese individuals with NAFLD [88]. They also assessed the effects of HIIT and MICT for 8 weeks in diabetic obese patients with NAFLD and found that both training modalities significantly reduced IHTG, visceral lipids, plasma ALT, plasma glucose, and improved insulin sensitivity, even though no differences were observed between both exercise modalities [96]. These results are consistent with Winn et al., who demonstrated a significant reduction in intrahepatic lipid (IHL) content after a 4-week training program with either HIIT or MICT matched for energy expenditure (~400 kcal/session) in patients with NAFLD. Nevertheless, the differences in IHL reduction were not significant between both exercise intensities (p = 0.25) [87].

Exercise Dose in NAFLD
The optimal dose of exercise prescription to achieve results for the proper management of NAFLD is not clear since differences exist regarding the amount of exercise per session, times per week, intensity, and the total amount of exercise to observe an improvement in subjects with NAFLD. One study found a significant correlation between the number of sessions per week and the absolute reduction in hepatic fat content (r = 0.52; p = 0.001) [93]. Programs of three sessions/week have shown optimal results regarding NAFLD resolution marked by an improvement in insulin sensitivity and a reduction in fasting plasma glucose in several RCTs with both aerobic and resistance exercise [82,84,85,88,[94][95][96].
There are differences in the duration of the intervention in training programs regarding their effectiveness in the management of NAFLD. Winn showed a significant reduction in intrahepatic lipid content with just 4 weeks of aerobic training in subjects with NAFLD [87]; however, most studies have evaluated 8-12 weeks of exercise to observe the effectiveness of the intervention to improve or resolve NAFLD [82,83,86,88,93,95,96]. Some studies have even extended up to 22 weeks [94] or 6 months of intervention and have achieved higher improvements in the metabolic parameters and the NAFLD score [89].

Optimal Exercise Modalities in NAFLD
Although various exercise modalities seem to improve or even resolve NAFLD, their prescription must be considered within the context of several aspects related to the patient, such as age, comorbidities, fitness status, and preferences [76], since aerobic and resistance exercise have different advantages and disadvantages. There exists more evidence of effectiveness for aerobic exercise than resistance exercise regarding the improvement in visceral adipose tissue, ALT, glucose, and lipids [94,95,97]. However, it requires higher cardiorespiratory fitness because it causes fatigue and less tolerance (particularly HIIT), which may lead to poor compliance. Moreover, patients with comorbidities, such as coronary disease and osteoarthritis (frequently in the knees), could limit their ability, even though moderate-intensity activities, such as brisk walking, jogging, and cycling, are simple and cost-effective [7,76].
On the other hand, resistance exercise requires less energy consumption and may be better tolerated in patients with poor cardiorespiratory fitness. On the downside, it frequently requires specialized machines and equipment coupled with a personal trainer, at least initially, to perform the exercises properly and reduce the risk of musculoskeletal injuries that may eventually compromise exercise compliance [76].

Exercise Adherence in NAFLD
Adherence to any type of exercise represents an issue for many people. In a study of patients with NAFLD, Stine et al. found 75% of patients failed to achieve the prescription of ≥150 min/week of physical activity. Lack of resources and education from their treating medical provider, physical discomfort, and time restrictions were the major barriers identified by patients [98]. Therefore, the modality of exercise, the number of sessions per week, and the intensity must be individualized according to the age, fitness, comorbidities, and preferences of each patient, seeking greater compliance in the long term by finding the most tolerable and enjoyable activities for each patient.   Abbreviations: NASH: non-alcoholic steatohepatitis; NAFLD: non-alcoholic fatty liver disease; CR: calorie-restricted; CHO: carbohydrates; E: exercise; HR: heart ratio, HRR: heart rate reserve; BP: blood pressure; FG: fasting glucose; TG: triglycerides; HOMA-IR: homeostasis model assessment of insulin resistance; HRQoL: heart-related quality of life; WC: waist circumference; WHR: waist-to-height ratio; VO 2 peak, peak oxygen consumption; RT: resistance training; HIAT: high-intensity interval aerobic training; MICT: moderate-intensity continuous training; NA: not applicable; HIIT: high-intensity interval training; IHL: intrahepatic lipid; CD: controlled diet; LGIMD: low glycemic index Mediterranean diet; PA1: physical activity 1; PA2: physical activity 2.

Strengths and Limitations
Our review was carefully revised to ensure that only RCTs were included, which deliver a high level of evidence, thus preventing selection bias. We assessed whether the exercise training was performed under supervision, ensuring correct compliance to the intervention. We only included studies that provided detailed information related to the exercise training modality, intensity, frequency, session duration, and intervention period. However, our review still has several limitations. This study focused primarily on the effects of exercise training, while the impact of studies on the effects of diet on NAFLD was seldom considered and, thus, the effect of diet coupled to exercise could not be evaluated; additionally, we excluded cohort studies. The heterogeneity of the studies regarding comorbidities of the study population, NAFLD stages, assessment of exercise modalities, intervention period, as well as ethnicity and outcome assessment, represents another limitation. The included studies measured different aspects, so that, although most of them evaluated changes in hepatic fat content with exercise training, others only evaluated biochemical parameters. Since only studies on adults were included, these results cannot be generalized to pediatric or adolescent populations. Finally, only studies published in English were included in the present review.
The intervention for most studies ranged between 8 and 12 weeks, and, therefore, the effects of the exercise training in the long term could not be determined. Furthermore, no study evaluated long-term outcomes after the intervention had ended. Therefore, future research should focus on evaluation of the effect of post-intervention exercise in participants who had a resolution of NAFLD with exercise training, and include comparison of studies that include combined intervention with those with exercise alone to evaluate the potential of exercise. Additionally, more variables should be measured, such as the ethnicity of the population, lifestyle habits, and pathological history, that can guide us to generate increasingly specific exercise strategies for NAFLD patients.

Conclusions
The implementation of physical activity showed a strong association with improvements in inflammation, steatohepatitis, and fibrosis, and a beneficial effect on liver function in experimental models. In addition, physical activity demonstrated other major benefits, e.g., the suppression of genes related to lipogenesis and inflammation, as well as upregulation of those related to lipid oxidation and the apoptosis pathway in the liver. Several exercise modalities were demonstrated to have a positive effect in clinical studies of NAFLD in humans. An optimal exercise prescription in terms of type, intensity, and dose that improves or resolves NAFLD has not been established; nevertheless, a dose-response relationship has been observed. Both aerobic exercise and resistance exercise have been demonstrated to reduce liver fat and improve insulin resistance, and blood lipids regardless of weight loss, although there is more evidence of positive effects for aerobic exercise. Resistance exercise is more feasible for NAFLD patients with poor cardiorespiratory fitness. Short-term training programs have proved to be effective, but the benefits may be lost in the long term without proper adherence to permanent lifestyle modification. Diet and exercise prescriptions for NAFLD should be individualized according to the preference, physical fitness, and comorbidities of each patient to promote sustained adherence to lifestyle changes. More effort and awareness-raising should be applied to encouraging an active lifestyle for a better impact on NAFLD patients, and, therefore, reduction in the burden associated with this growing public health problem.

Conflicts of Interest:
The authors declare no conflict of interest.